Body weight and energy balance are maintained by neurons in the hypothalamus. Insulin signaling in hypothalamic neurons plays a pivotal role in preventing excessive energy accumulation and obesity, since mpairment or loss of hypothalamic insulin signaling is sufficient to cause energy imbalance leading to obesity and type 2 diabetes (T2D). Recent advances show that persistent nutrient overload induces hypothalamic insensitivity to insulin; however, the molecular basis for this is unclear. Following our previous discovery that pro-inflammatory nuclear transcription factor NF-KB and its upstream activator IKKp are activated in peripheral tissues by a high-fat diet to induce local insulin resistance, this proposal will nvestigate the role of IKKp/NF-KB in hypothalamic dysregulation of insulin signaling and energy balance. Preliminary results show that high-fat diet activates IKKp/NF-KB in mouse hypothalamus, and activation of KKp/NF-KB impairs hypothalamic insulin action both in vitro and in vivo. Animal tests further show that the selective activation of IKKp/NF-KB in mediobasal hypothalamus induced weight gain, while the suppression of this pathway in insulin-sensitizing hypothalamic neurons protected against dietary obesity. Based on these research contexts and preliminary data, this proposal hypothesizes that chronic challenges of nutritional excess activate IKKp/NF-KB in the hypothalamus, desensitize hypothalamic neurons to insulin, and cause energy imbalance leading to obesity and T2D. This hypothesis predicts that suppressing hypothalamic KKp/NF-KB could reverse or prevent these diseases. The following three specific aims will be performed to test this hypothesis: (1) determine the linkage of excessive nutrition with IKKp/NF-KB in the hypothalamus; (2) elucidate the action of IKKp/NF-KB on hypothalamic insulin signaling; (3) assess metabolic outcomes of heuronal IKKp/NF-KB manipulations in insulin-responsive hypothalamic nuclei and neurons. To achieve these aims, our established in vitro and in vivo models and particularly the approaches of site-directed transgenesis and conditional gene knockout will be empoyed to analyze IKKp/NF-KB, insulin signaling and metabolic phenotypes. Completion of these aims will advance our knowledge about the brain pathogenesis of obesity-T2D, provide a molecular basis for developing new therapeutic and preventive strategies, and also establish a new model to study the nutrition-inflammation axis in the brain underlying nutritional diseases.